GATA2 negatively regulates PTEN by preventing nuclear translocation of androgen receptor and by androgen-independent suppression of PTEN transcription in breast cancer

The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) plays important roles in tumor development and progression. Among many functions, PTEN negatively regulates the AKT anti- apoptotic signaling pathway, while nuclear PTEN affects the cell cycle by repressing the mitogen- activated protein kinase pathway. However, the regulation of PTEN expression is still not well understood. We previously reported that androgen receptor (AR) activates PTEN transcription in breast cancer cells. Here, we found that the transcription factor GATA2 (GATA binding protein 2) is overexpressed in non- cultured human breast carcinomas and is negatively correlated with PTEN expression. We then showed GATA2 promotes breast cancer cell growth and stimulates AKT phosphorylation by inhibiting PTEN transcription. We mapped a GATA2- binding site in the PTEN promoter, whereby GATA2 not only blocks AR- induced PTEN expression by preventing AR nuclear translocation, but also directly represses PTEN transcription independent of AR. Most importantly, for the first time, we have discovered a novel reverse regulation within the traditional PTEN/ AKT signaling pathway, whereby AKT induces GATA2 with consequent decreased PTEN transcription, likely germane in tumor invasion and metastases but not initiation.